Animal studies indicate that the local anesthetic procaine specifically activates limbic structures. Human studies suggest that acute intrave- nous procaine induces a rage of psychosensory and emotional experiences associated with increased temporal lobe fast activity, decreased occipi- tal alpha activity, and increases in ACTH, cortisol and prolactin, but not growth hormone. We are currently studying the effects of acute intravenous procaine on regional cerebral blood flow (rCBF) measured with oxygen-15 water and positron emission tomography. In the 10 patients with mood disorders and 32 normal volunteers studied thus far, data analysis with statistical parametric mapping (SPM) has revealed that procaine significantly increases rCBF bilaterally in the anterior tempo- ral lobes (aTL), inferior frontal lobes (iFL) and anterior cingulate gyri (aCG) in a (amygdalofugal) pattern remarkably similar to that of the amygdala and its efferents as observed in primates. Visual inspection of individual PET subtraction images with coregistered magnetic resonance images qualitatively confirmed this pattern. Subjects with intense procaine-induced visual hallucinations, compared with those without, had increased rCBF in the mesial occipital lobes in addition to more robust amygdalofugal activation. Compared with those without, subjects with intense procaine-induced anxiety had increased amygdalofugal activation, while those with intense procaine-induced euphoria had a more intense activation of the septal area and hypothalamus. These data also suggest that amygdalofugal limbic and paralimbic structures in the aTL, iFL, and aCG may comprise important elements of the neural substrate of emotional experiences. Furthermore, patients with mood disorders compared with controls had not only decreased resting rCBF in the frontal lobes and left amygdala, but also blunted amygdalofugal rCBF responses to procaine, despite similar clinical responses to controls. Such anterior temporal and frontal hypofunction could mediate the emotional and cognitive disturbances observed in affective disorders.